Microgel particles, which are nanoscopic or microscopic colloidal particles of cross-linked polymer, have been investigated for a number of different potential applications. Particular examples include their use as micro-reactors for the template synthesis of inorganic nanoparticles, as optically active materials including lenses and photonic crystals, and as drug delivery systems (Das et al. Annual Reviews of Materials Research, 2006, Vol. 36: 117-142).
Microgel particles have also been used for the preparation of photonic hydrogels, especially photonic hydrogels capable of manipulating photons in the visible and near-infrared spectrum (see Cai et al. Macromolecules, 2008, Vol. 41: 9508-9512). More specifically, Cai et al. describe photonic hydrogels derived from thermally-responsive, vinyl functionalized microgel particles. The microgel particles, which are formed from PEG-polymers, are cross-linked by interlinking polymer chains formed by the polymerization of ethyleneglycolacrylate (PEGA) and/or acrylamide monomers. Upon photo-initiation, the ethyleneglycolacrylate (PEGA) or acrylamide monomers react with the vinyl groups present on the microgel particles and polymerise to form interlinking poly(PEGA) or poly(acrylamide) polymer chains. The result is a hydrogel composed of microgel particles connected together by interlinking polymer chains of varying length.
One particular application of biocompatible microgel particles is their potential utility for the replacement or repair of injured, degenerated or inappropriately formed load-bearing soft tissues, such as, for example, intervertebral discs and the tissues found in articular joints (such as the elbow, knee, hip, wrist, shoulder and ankle). These soft tissues need to be able to bear significant loads and changes in pressure. For example, the pressures experienced within human intervertebral discs can vary from about 0.5 MPa when sitting to about 2.3 MPa when lifting a 20 kg weight. Consequently, the ability of soft tissues, such as intervertebral discs, to bear varying biomechanical loads is essential for the normal operation of the body.
The principle load-bearing tissue of the intervertebral disc is the disc-shaped nucleus pulposus, which forms the centre of an intervertebral disc. The nucleus pulposus consists of chondrocytes (cartilage producing cells) within a matrix of collagen and proteoglycans. Articular cartilage, which is the tissue covering bony ends of articular joints, has a similar composition to that found in the nucleus pulposus. The proteoglycans have a high negative charge density and are responsible for the high swelling pressure of the nucleus pulposus. The nucleus pulposus is a natural ionic hydrogel and contains about 75% water in adults. The proteoglycan content gradually decreases with age due to natural degeneration, and this can result in the formation of three dimensional channels known as “clefts”. The formation of clefts provides weak points or voids in the structure of the disc, which can eventually become detrimental to the overall shape, form, dimensions and performance of the disc, particularly when a pressure is applied.
Any injury, degeneration or malformation in load bearing tissues can result in significant pain and lack of mobility. A major proportion of all intervertebral discs in the lower part of the spine show signs of degeneration by the age of 50. This can result in chronic back pain, which is a major cause of morbidity and absence from work.
The treatment of damaged load-bearing soft tissues, such as intervertebral discs or articular joints, is usually directed at symptomatic relief of the pain. In severe cases, surgical intervention may be necessary to remove some of the damaged tissue and insert a prosthetic replacement. Surgical intervention is effective in relieving pain, but it can result in the damage of adjacent tissues and alterations in the biomechanical/load-bearing properties of the tissue concerned. In addition, surgical intervention may require a protracted stay in hospital and significant morbidity for the patient concerned.
A material science approach to address the problem of degenerating intervertebral discs and other load bearing tissues involves injecting molecules that polymerise at the site of injection. The polymer deposit formed provides additional mechanical strength to the bolster the remaining tissue. One particular example described in WO2000/062832 is the in situ polymerisation of poly(ethylene glycol) tetra-acrylate in the nucleus pulposus of the intervertebral disc. Another example involves the injection of chitosan into the nucleus pulposus and allowing it to polymerise. Chitosan is a positively charged polysaccharide that is soluble in water at low pH. It undergoes a solution-to-gel transition when the pH is increased. It has therefore been contemplated that chitosan may be injected as a low pH solution and then allowed to form a gel when it is exposed to a higher pH in vivo. The gel that forms in vivo is uncharged and forms a polymer network that occupies the whole volume of the injected solution. Hence, it becomes a macrogel through in situ polymerisation.
The provision of injectable materials that can be used to treat damaged or degenerated load-bearing tissues, such as intervertebral discs, is a major challenge. It should also be appreciated that a key criterion for such materials is that their mechanical properties replicate that of the normal healthy load-bearing tissue as closely as possible.
WO2007/060424, the entire contents of which are incorporated herein by reference, describes the use of pH-responsive microgel particles for this particular application. The use of biocompatible pH-responsive microgel particles provides many attractions. In particular, the microgel particles can be injected in a compacted (or “non-swollen”) configuration by controlling the pH of the injection medium. However, once present in the body, the pH will typically adjust to the normal physiological pH of the tissue due to the natural buffers present in physiological fluids. At physiological pH values, the polymer that forms the pH-responsive microgel particles undergoes a conformational change, which causes the microgel particles to hydrate and swell. The swollen microparticles then provide a gelatinous mass which fills any regions of degenerated tissue and provides additional mechanical support to the tissue concerned.
However, despite the attractions of this approach, the mechanical properties of the gel is not optimal and there is a tendency for the microgel particles to dissipate/migrate away from the injection site, so there still remains a need for alternative injectables that are capable of providing further improved biomechanical support for the treatment or replacement of damaged or degenerated load-bearing tissues.
It is therefore an object of the present invention to obviate or mitigate one or more of the problems of the prior art, whether identified herein or elsewhere. In particular, it is an object of the present invention to provide a further improved method for repairing damaged and degenerated load-bearing tissue.